Pulmonary emphysema is a common disease in which destruction of the lung's gas-exchange structures (alveoli) leads to inadequate oxygenation, disability and, frequently, death. Lung transplantation has previously provided the only means of remediation.
Alveoli are formed by the developmentally regulated subdivision of saccules that constitute the gas-exchange region of the immature lung. The molecular signals responsible for the formation of septa and for their spacing are poorly understood. However, in the rat retinoids may play a key regulatory role. Fibroblasts rich in vitamin A (retinol) storage granules occupy a large fraction of the alveolar wall when septa are being formed. During the same period, the concentration of cellular-retinol binding protein I, cellular retinoic acid-binding Protein I, and nuclear retinoic acid receptor-.tau. mRNA peak in the lung. Treatment with dexamethasone, a glucocorticosteroid hormone, prevents septation in a seemingly irrevocable fashion, and diminishes the expression in the lung of cellular retinol-binding protein and retinoic acid receptors-.beta. mRNA.
The use of all-trans retinoic acid for treatment of diseases relating to growth and tissue maintenance has previously been known. Retinoic acid receptors belong to a family of nuclear receptors that includes receptors for steroids, thyroid hormone, and calcitriol. It has previously been disclosed that retinoic acid prevents inhibition of alveoli in rats arising from exposure to dexamethasone. (Am. J. Physiol. 270: L305-L310 (1996)). There is no teaching therein regarding use of retinoic acid for treatment of emphysema.
U.S. Pat. No. 3,171,781 teaches use of vitamin A and guaiacol for treatment of contagious "air sac disease" in fowl. It is not clear what the pathology or nature of the infectious agent of the disease condition might have been. There is no teaching therein regarding retinoic acid or treatment of emphysema.
U.S. Pat. No. 4,606,920 teaches use of vitamins A and C for treatment of inflammatory changes in the bronchial mucosa. There is no teaching seen therein regarding treatment of diseases involving the alveoli.
U.S. Pat. No. 5,534,261, which is incorporated herein in its entirety as though fully copied herein, teaches use of retinoic acid to prevent formation of adhesion between organ surfaces in body cavities, especially in the peritoneal cavity. No teaching of use for treatment of emphysema is seen therein.
U.S. Pat. No. 5,556,611, which is incorporated herein in its entirety as though fully copied herein, teaches use of retinoic acid and esters thereof in the form of aerosols for treatment of mucosal diseases. Diseases to be treated by use of such aerosols include bronchial carcinoma, acute and chronic bronchitis, acute and chronic functional disturbances due to impairment of the trachealbronchial epithelium following inhalation of dusts and gases, bronchopulmonary dysplasia of newborns and carthagena syndrome. There is no suggestion therein that retinoic acid, its esters or analogues thereof can be administered for treatment of emphysema, which arises from destruction of the lung alveoli.